JPS63227549A - Preparation and isolation of (r)-2- hydroxyphenylbutyric acid and esters - Google Patents

Abstract

Disclosed herein is a novel compound, (L)-menthyl 2-oxo-4-phenylbutyrate, and an improved process for making and isolating a substantially pure compound of the structural formula: <CHEM> wherein Y is hydrogen or (L)-menthyl the improvement which comprises: a) stereoselectively reducing (L)-menthyl 2-oxo-4-phenylbutyrate by contacting said compound with with S-Alpine borane, b) stereoselectively isolating (L)-menthyl-(R)-2-hydroxy-4-phenylbutyrate by crystallization, and optionally hydrolyzing the so obtained ester; and further comprises optionally esterifying the so obtained acid by contacting said acid with a C1-C6 alkanol in the presence of acid. u

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for preparing and isolating (R)-2.hydroxy-4-phenylbutyric acid and esters.

[Prior Art and Problems] Recent advances in medical science have shown that angiotensin converting enzyme (A
CE) and have yielded compounds that may be useful in the treatment of hypertension in humans. Many of these compounds, such as enalapril, ramipril, cilazabril, quinapril, and lisinabril, have common general structural features that have been found to contribute to enhanced end-use properties. A common feature of such compounds is the (S) enantiomer of the 2-amino-4-phenylbutyric acid moiety or esters thereof having structural formula (1). where Y is hydrogen or (C+-Ca)alkyl and Q is the remainder of the desired ACE inhibitor. The corresponding enantiomers with the (R)-configuration about the chiral center consisting of the 2-position of the butyrate moiety lack similar potency as ACE inhibitors and antihypertensive agents and are less desirable for end-use use. I found out that there isn't.

ACE inhibitors of structure 1 are (R)-2-hydroxy-4-phenyl under standard conditions well known in the art calculated to effect direct SN2 substitution of the 2-hydroxy group by an amine. It can be made by reacting a suitable ester of butyric acid with a suitable amine. Such reaction conditions are suitable for ethyl (R)-2-hydroxy-4-
Urbach (lJr”) using trifluoromethanesulfonic acid ester of phenylbutyrate as a reactant in this synthesis.
Tetrahedron Letters, Vol. 25, p. 1143 (1984)
)]. Therefore, ethyl(R)-2 is useful for use as an intermediate in the synthesis of various ACE inhibitors.
It would be desirable to have a method for preparing and isolating -hydroxy-4-phenylbutyrate and similar compounds.

Most available synthetic methods for these alkyl esters of (R)-2-hydroxy-4-phenylbutyric acid yield racemic mixtures of the (R)- and <S>-enantiomers present in essentially equal amounts. The procedure required to resolve the (R) enantiomer proved to be difficult and time consuming. For example, D, Biqu
[Ann.

de Chemie Vol. 20, p. 146 (1933)]
. In that case, since the (L)-menthyl moiety functions as a resolving agent, (L)-menthyl (R)-2-hydroxy-4
- It has been found that phenylbutyrate can be selectively crystallized from racemic mixtures. However, this resolution requires a long and difficult crystallization procedure, and stereoisomers of the (R)-configuration are isolated in low yields.

[! ! Means for Solving the Problem] The present invention provides a novel compound (L)-menthyl 2-oxo-4-
By utilizing a synthetic method involving phenylbutyrate, a method has been developed that allows for the preparation and isolation of (R)-2-hydroxy-4-phenylbutyric acid and its esters in an uncomplicated and efficient manner.

In terms of its composition, the present invention relates to a novel compound (L)-menthyl 2-oxo-4-phenylbutyrate of structural formula (2). This compound is (12-hydroxy-
4-phenylbutyric acid, its esters, and structural formula (1)
It is useful as an intermediate in the synthesis of ACE inhibitors containing the moiety described in . (L)-Menthyl 2-oxo-4-phenylbutyrate (2) is produced by condensing (L)-menthol with methyl chloroglyoxylate and converting the resulting mixed oxalate, methyl ethanedionate-(L)-menthyl ester, into the resulting mixed oxalate. It is made by reaction with phenethylmagnesium bromide by standard procedures well known in the art. Product (2) is purified and isolated using standard column chromatography and crystallization procedures.

Another aspect of the invention is the (R)-2-hydroxy-4- A novel and efficient method for the stereoselective synthesis and isolation of phenylbutyric acid and selected esters.

The term (CI-Co)alkyl intends an alkyl group containing 1-6 carbon atoms in a straight or branched configuration. When ■ is (L)-menthyl, the compound is (L)-menthyl (R)-2- represented by the structural formula (3a).
Hydroxy-4-phenylbutyrate.

More particularly, the method aspect of the invention provides novel compounds (2)
by stereoselective or chiral reduction of the corresponding (R)
-configuration alcohol (3a), which is then hydrolyzed to its acid and re-esterified to the desired ester intermediate suitable for the preparation of ACE inhibitors. These reactions are shown in Reaction Route A.

Reaction Route A 9 In the formula, Y' is hydrogen and Y''' is (CI-Co)alkyl.

To perform the above stereoselective or chiral reduction, the compound (
2) is reacted with a chiral reducing agent such as S-alpine borane. Stereoselective reduction of asymmetric ketones can be carried out through the use of a variety of chiral reducing agents. These reducing agents generally consist of reducing agents that favor one stereoisomer over the corresponding enantiomer as the product of reduction. In the present invention, by contacting compound (2) with S-alpine borane or a chiral reducing agent having an equivalent function, compound (3a) can be subjected to a stereoselective reduction favoring its enantiomer as a reaction product. .

Preference is given to using S-alpine borane.

Compound (2) is mixed with 12 equivalents of S-alpine borane at a temperature range of about -20°C to about 10°C, preferably neat, or in tetrahydrofuran (T) IF.
), diethyl ether, or dimethoxyethane (DM
Compound (2) is reacted with S-alpine borane by contacting it in the presence of an inert solvent such as E). Reactions are generally run for 17 days. The reduction product thus produced contains the (R) and (S) enantiomers of the corresponding alcohol, but at least 80x of the product
is of (R)-configuration, that is, compound (3a).

Utilizing the properties of (L)-menthyl ester as a resolving agent, by stereoselective crystallization techniques well known in the art,
The separation of compound (3a) from its enantiomers is carried out. Chiral reduction of compound (2) is performed by reducing the compound (
The resolution of compound (3a) proceeds faster and in higher yields than resolution from essentially equal amounts of enantiomeric mixtures because the amount of 3a) yields a greater reduction product than the amount of enantiomer. Although (L)-menthyl ester is the preferred resolving agent for this route, other functionally functional esters also have high selectivity to the desired enantiomer upon chiral reduction and subsequent crystallization steps. Any agent that functions efficiently as a dividing agent can be used. An alternative resolving agent is (
L)-8-phenyl methyl ester, and various N derived from the protection and reduction of (D)- or (L)-amino acids.
- Includes esters incorporating protected (0)- or (L)-amino alcohols.

A preferred solvent for separating compound (3a) from its enantiomers is a (C+-Ca)alkanol/water mixture in which water accounts for up to about 20x of the mixture.

The term (C+-Ca)alkanol means alkanols of 1-6 carbon atoms in straight or branched configuration, such as methanol, ethanol, propatool, isopropanol, etc., or mixtures thereof. Aqueous methanol is most preferred. However, other solvents can also be used, including non-polar solvents such as (C4-Ca) alkanes, which allow the (L)-menthol ester to function as a resolving agent. The term (C4-Cal)alkane means straight-chain or branched-chain alkanes of 4-8 carbon atoms, such as butane, pentane, hexane, heptane, octane, or mixtures thereof. During crystallization, temperatures of about -1 cC to about 10C are preferred.

(L)-Menthyl (R) synthesized and isolated using the present invention
)-2-hydroxy-4-phenylbutyrate (3a)
When further reacted, the corresponding (R)-2-hydroxy-4-phenylbutyric acid (3b) and ethyl (R)-2-
Its C+ including hydroxy-4-phenylbutyrate
-Ca alkyl esters (3c) are produced.

Compound (3b) is made by hydrolysis of compound (3a) with Lewis base by standard procedures well known in the art. The preferred reagent for this reaction is LiOH, but many other bases with similar functionality can be used, such as NaOH1KO)I, or CO2CO3.

Esterification of compound (3b) with the appropriate alcohol by standard procedures well known in the art yields the (C+-Ca) alkyl ester (3C). Ethyl ester is most preferred. Esterification is preferably carried out by contacting compound (3b) with a suitable (C+-Ca)alkanol in the presence of an acid catalyst. For example, ethyl (R)-2-hydroxy-4-phenylbutyrate is made by reacting compound (3b) with ethanol in the presence of an acid such as HCI.

Various compounds with activity as ACE inhibitors and antihypertensive agents have been prepared using formula (3c) under standard conditions well known in the art, calculated to effect SN2 substitution of the (R1) reflate by an amine. It is made by reacting the trifluoromethanesulfonic acid ester of the compound with a suitable amine.

Esters of N-substituted-(S)-2-amino-4-phenylbutyric acid are thus produced, which are optionally hydrolyzed to the acid.

EXAMPLES The following examples serve to illustrate method aspects of the invention. All temperatures are stated in degrees Celsius.

Example 1 (S)-Menthyl 2-oxo-4-phenylbutyrate Step A: Methyl ethanedionate-(L)-menthyl ester 2:1 methylene chloride/(L) in 450 ml of lysine
- A solution of 78.14 g (500 mmol) of menthol is cooled to 0°C.

This solution is lubricated with a solution of 48.9 ml (530 mmol) of methyl chloroglyoxalate in 100 l of methylene chloride. Stir overnight while the mixture warms to ambient temperature. Filter the mixture and wash the precipitate with ethyl acetate. Concentrate the filtrate in vacuo, take up in hexane and refilter. 95°C, 0.01 mm using a Kugelrohr apparatus
Concentrate and distill the filtrate with J. The distilled material contains a crystalline solid which is filtered off and discarded, leaving 17.9 g of analytically pure mixed ethanedionate methyl-(di)-menthyl ester in a yield of 97.3%. Physical properties of the product include:

[α]. "8=+77.6' (c=1.2.
CHCl3)'HNMR (300MHz): 0.7
9(d,3)1. , Hz7.2 Hz＞: 0.91(
d.

3H,, Hz6.8 Hz): 0.93(d, 31
1. , Hz6.6 Hz): 0.85-1.21(
Composite, 3N>: 1.54 (td, 2L, Ia=11
．． 5) 1z, , Ib = 3.1 Hz): 1.72 (composite doublet, , l: 11.6 Hz): 1.90 (
Doublet septet, IH,, Ia = 7.0 Hz
, , Ib=2.7 Hz): 2.05' (composite doublet, IH, Hz11.7 Hz>: 3.90 (S
, 3H); 4.86 (td, IH, , Ia=10.
9 Hz, Ib=4.5 Hz), IR (film): 2950.2920.2870.1770.1
? 40. +460°1320, 1200.11?0.
1150.950 cm-', analysis: C+3H220a
(D calculated value: C=64.44X; 1(=9.15L
Measured value: C=64.09%: )Hz8.98χ.

Step B: (L)-Menthyl 2-oxo-4-phenylbutyrate 24.2 g (100 mmol) of ethanedionate methyl-(shi)-menthyl ester in 40 ml of dry THF
In addition, newly prepared phenethylmagnesium bromide (10
0 mmol) solution while maintaining the reaction temperature between -20°C and -25°C. (Warm the addition funnel slightly during the addition to keep the phenethylmagnesium bromide in solution.) The addition requires a total of 45 minutes. After adding the phenethylmagnesium bromide, the mixture is stirred for 30 minutes while warming to ambient temperature. To this mixture, IN HCj 10
01, 100 ml of ethyl acetate, and 20 ml of brine are carefully added one after another. Separate the organic layer and IN IIc
I 50ml, brine 101, saturated NaHCO350ml
, and brine 501 one after another. Organic solution Hg5Oa
Dry, filter and concentrate in vacuo. The yellow oily residue was diluted to 100 ml with hexane and cooled to -30<0>C before seeding with crystals of (L)-menthyl 2-oxo-4-phenylbutyrate. Once crystallization started, the mixture was kept at -20°C overnight. The crystals are collected and dried to yield (cy)-menthyl 2-oxo-4-phenylbutyre-) 12.1y, (3B, 3χ). The mother liquor is concentrated in vacuo and chromatographed on silica on a 30 mm column, eluting with 3x ethyl acetate/hexane. The desired fractions are combined, concentrated and crystallized as above to yield an additional 2.0 g (11x) of analytically pure product. Physical properties of the product include: Melting point, 51-53°C [α]. ”
B=-66y4' (c=1-1+ CHCl3)'H
NMR (300MHz): 0.75(d, :01.,
l”7.2 Hz): 0.89 (d.

3H,,l=7.5)1z): 0.92(d,3H
,, l near, 2 Hz): 0.8? -1,16 (composite, 3N); 1.51 (composite triblet, 2H,,1
=10. ．． 4fiz); 1.70 (composite doublet,
2)1. ．． 1=11. o Hz); 1.84 (Doublet Veracit, IH,, Ia = 7.0 Hz, ,
Ib=2.8Hz); 2.03 (composite doublet, I
H,,1=11.4 Hz); 2.95(t, 2H,
, l near, 5) 1z): 3.16(t, 2H,,H
z7.5 Hz): 4.81 (td, IH,, Ia=
11.0 tlz,, 1b=4.6)1z);7.1
? -7,25 (aromatic.

5H), IR (KBr): 2960.2930.2
870.1725.1460°1260, 1070.7
00 cl', calculated value of analysis C2ot12803: C=
75.91χ: Hz8.92%, measured value: C=75
．． 63%; Hz 8.991 Example 2 (L)-0.5 M S- in Menthyl (R12-Hydroxy-4-phenylbutyrate Tetrahydrofuran (T) IF)
A solution of 180 ml (80 mmol) of alpine borane is concentrated to 60 ml at 30'C/120 mmHg. The flask containing S-alpine borane is purged with N2 and cooled to -20<0>C. 17.9 g (56.5 mmol) of finely ground (L)-menthyl 2-oxo-4-phenylbutyrate are added all at once to the cooled solution. The mixture is stirred vigorously for 1 hour at -20°C to dissolve the ketoester. The resulting solution is left at 0°C for 5 days. 20 ml of acetaldehyde are added and the mixture is stirred for 1 hour while warming to ambient temperature. The volatiles were removed in vacuo and the residue was incubated for 1 hour using a Kugelrohr apparatus.
Subject to distillation conditions (70'C/1 mm 1G). The undistilled oil is dissolved in 100 ml of diethyl ether, lubricated with 4.8 ml (80 mmol) of ethanolamine and the solution is brought to a boil. A precipitate forms immediately. The mixture is stirred for 10 minutes and filtered through flash silica 751. Add 150 ml of diethyl ether to the silica
When the eluate is concentrated in vacuo to an oil, the oil crystallizes almost immediately. crystalline solid hexane 150
Dissolve and concentrate to 75 ml and seed with crude (cy)-menthyl (R)-2-hydroxy-4-phenylbutyrate.

The seeded mixture is cooled to 20° C. overnight.

When the crystals formed are filtered and dried, (1 door menthyl (I)
+)-2-hydroxy-4-phenylbutyrate11.
2 g with a yield of 62.3X. Physical properties of the product include:

Melting point = 85-86°C [αlpAMB='-63,1' (c=0.85.
CHCl3)'HNMR (300MHz): 0.
77(d,3H,,l=6.67)1z):0.90
B(d, 3H,, l=8.25 Hz); 0.913(
6,3H,,l:5.70 Hz); 0.80-1.
14 (composite, 3N); 1.38-1.58 (composite, 2
N); 1.68 (wide area 5IIHI); 1.72 (wide area s, 1) 1): 1.84-2.18 (combined, 4H):
2.68 (ddd, IH,, 1a=14.49 Hz
+, Ib=10.85) 12°, lc:4.88H
z): 2.80 (ddd, IH,,1a=14.49
Hz+, Ib=10.96 Hz, Ic=7.0
5 Hz); 2.92 (d, IH,, I=5.3
0 Hz); 4.1? (ddd, IH,,1a=
7.72 Hz,, 1b=5.98 tlz,, Ic=
4.55 Hz); 4.79 (td, 1) 1. ,Ia=
10.58 Hz+, Ib=4.39 Hz): 7.
18-7.33 (aromatic, 5)1), IR (KBr)
345 (1,2950,2920°2860, 1?
25. 1500. +450. 1220. 11
B0. 1100°690 cm-', analysis C2oH
Calculated value of 3o03: C=75.46χ;)1=9.5
0X, 1llll constant value: C=75.13%; )l
=9.59%.

Similarly, (L)-menthyl (R)-2-hydroxy-4
- Stereoselective crystallization of phenylbutyrate is also carried out using methanol-water as solvent, where the water accounts for up to about 20X of the solvent.

Example 3 (R)-2-hydroxy-4-phenylbutyrate (3.18 g of menthyl (R)-2-hydroxy-4-phenylbutyrate (10,
0 mmol) solution, add 12.5 ml of IM LiOH (
12.5 mmol) and warm the mixture to dissolve the resulting precipitate. The mixture is stirred overnight at ambient temperature under a nitrogen atmosphere, producing a precipitate that does not dissolve upon warming. Add water 201 to the mixture to dissolve the precipitate,
Remove ethanol in vacuo. The aqueous residue is washed with 2 portions of diethyl ether 650, acidified and extracted with 3 portions of 30 ml each of methylene chloride. The extracts are combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue is dried under vacuum and dissolved in dry ethanol 501. The solution is saturated with gaseous HCl and left overnight at ambient temperature. The solution was concentrated in vacuo and diluted with ethyl acetate and saturated NaH.
Distribute among COs. Wash the organic layer with salt water and add anhydrous Mg
Dry with SO4 and concentrate in vacuo. The residue was distilled using a Kugelrohr apparatus at 120'C/1 mml to yield 1.60 g of ethyl (R)-2-hydroxy-4-phenylbutyrate in a yield of 76.0! occurs in Physical properties of the product include:

[α]DAM" = -19,4' (c = 1.4 + C
HCl3) Analysis Cl2HI603 (D calculated value: C=
69.20I H=7.681 Measured value: C=69.1
11; H=7.75%.

It will be understood that the foregoing detailed description has been set forth for purposes of illustration and that changes may be made without departing from the spirit or scope of the invention.

Applicant: Merrell Dow Pharmaceuticals, Inc.

Claims (1)

[Claims] 1. Compound (L)-menthyl 2-oxo-4-phenylbutyrate. 2. In the method for preparing and isolating a substantially pure compound of the structural formula ▲ mathematical formula, chemical formula, table, etc. ▼ [wherein Y is hydrogen or (L)-menthyl] (a) (
L)-menthyl 2-oxo-4-phenylbutyrate is stereoselectively reduced by contacting it with S-alpine borane; and (b) by crystallization (L)-menthyl (R)- An improved process comprising the steps of stereoselectively isolating 2-hydroxy-4-phenylbutyrate and, if necessary, optionally hydrolyzing the ester thus obtained. 3. Claim 2, wherein Y is (L)-menthyl
Section method. 4. The method of claim 2, wherein Y is hydrogen. 5. (R) obtained by the method described in claim 2
The method of claim 2, wherein -2-hydroxy-4-phenylbutyric acid is esterified to a C_1-C_6 alkyl ester by contacting this compound with a suitable C_1-C_6 alkanol in the presence of an acid. . 6. The method of claim 5, wherein (R)-2-hydroxy-4-phenylbutyric acid is converted to ethyl (R)-2-hydroxy-4-phenylbutyrate. 7. C_1-C_6 where water accounts for up to about 20% of the solvent
4. The process of claim 3, wherein (L)-menthyl (R)-2-hydroxy-4-phenylbutyrate is stereoselectively isolated by crystallization from a solvent consisting of an alkanol/water mixture. Claim 3, wherein (L)-menthyl (R)-2-hydroxy-4-phenylbutyrate is stereoselectively isolated from C_4-C_8 alkanes by crystallization.
Section method. 9. A process for the preparation of (L)-methyl 2-oxo-4-phenylbutyrate, comprising reacting ethanedionic acid methyl-(L)-menthyl ester with phenethylmagnesium bromide.